The main long-term objective of this Mentored Clinical Scientist Development Award is to provide the candidate with the guidance and training necessary to successfully make the transition to an investigator with an independent research program. This goal will be accomplished primarily through mentored bench work with a focus on broadening the knowledge and technical expertise of the applicant in the areas of cellular and molecular tumor immunology. Instruction in proper scientific method and procedure including reporting of data through publication will be provided. The applicant will also be provided the opportunity to become an interactive member of the broader scientific community through presentation of data at scientific meetings and participation in seminars and journal clubs. The research proposal is focused on an investigation of the role of negative regulatory T cells in a mouse tumor model. These studies are based upon the observation that transient elimination of negative regulatory T cells, using an antibody specific for CD75s, results in spontaneous tumor regression and lasting anti-tumor immunity. The proposed studies are designed to elucidate the mechanism by which model tumors evade immune destruction and the role that negative regulatory T cells play in this process. Since immunological tolerance to tumor antigens represents a major hurdle in the development of efficacious tumor vaccines, a thorough understanding of this system may contribute to both our basic understanding of tumor immunology and the successful implementation of tumor immunotherapy. Three hypothesis based specific aims are presented including experimental design, predicted outcomes, and potential problems. These aims propose to investigate the role that negative regulatory T cells play in the establishment of immunological tolerance to tumor antigens and the fashion in which their elimination can result in tumor rejection.